Regulatory T cells as a biomarker for response to adalimumab in rheumatoid arthritis Dao X. Nguyen, BSc, Alice Cotton, RN, BSc, Laura Attipoe, MBBS, Coziana.

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Regulatory T cells as a biomarker for response to adalimumab in rheumatoid arthritis Dao X. Nguyen, BSc, Alice Cotton, RN, BSc, Laura Attipoe, MBBS, Coziana Ciurtin, MBBS, PhD, Caroline J. Doré, BSc, Michael R. Ehrenstein, MBBS, PhD Journal of Allergy and Clinical Immunology Volume 142, Issue 3, Pages 978-980.e9 (September 2018) DOI: 10.1016/j.jaci.2018.04.026 Copyright © 2018 The Authors Terms and Conditions

Fig 1 Adalimumab-driven increase in CD4 Treg cells in PBMCs from patients with RA in vitro predicted subsequent clinical response to therapy. A, Representative FACS plot indicating the percentage of CD4+Foxp3+ Treg cells in PBMCs stimulated with adalimumab in vitro from a patient who subsequently responded and a patient who did not respond to adalimumab therapy assessed at 3 months. The right-hand panel shows that Foxp3+ CD4 T cells cosegregate with CD127loCD25hi CD4 T cells. The corresponding cumulative data of Treg-cell frequency in PBMCs from patients who responded (n = 14) or not (n = 5) to adalimumab therapy cultured with adalimumab or etanercept. B, Receiver-operating characteristic (ROC)-curve analysis of the percentage increase in Treg cells predicting clinical response (n = 19). C, Serum CRP before and after therapy in patients divided according to whether adalimumab increased Treg-cell frequency by more than 40% in the baseline sample in vitro (n = 19). CRP values for 2 responding patients who temporarily stopped their adalimumab at 6 months because of infection come from data collected between 6 and 9 months. CRP, C-reactive protein. *P < .05, ***P < .001 by paired t test. Journal of Allergy and Clinical Immunology 2018 142, 978-980.e9DOI: (10.1016/j.jaci.2018.04.026) Copyright © 2018 The Authors Terms and Conditions

Fig E1 A, Correlation between the change in CD4 Treg-cell frequency (proportion of CD4+ T cells) in PBMCs from patients at baseline cultured with adalimumab in vitro and the change in frequency of peripheral blood Treg cells in the same patients after 3 months of adalimumab therapy. B, Absolute number of Treg cells on day 3 from PBMCs from patients who responded (n = 14) or not to adalimumab therapy assessed at 3 months (n = 5) cultured with either anti-TNF agent. C, Percentage of Treg cells in PBMCs at baseline from patients who responded to therapy (n = 14) divided according to whether they were treated with methotrexate in combination with adalimumab. *P < .05, **P < .01 by paired t test. Journal of Allergy and Clinical Immunology 2018 142, 978-980.e9DOI: (10.1016/j.jaci.2018.04.026) Copyright © 2018 The Authors Terms and Conditions

Fig E2 Increased monocyte membrane TNF expression and adalimumab binding predicted therapeutic response. A, Correlation between the change in the percentage of Treg in vitro stimulated by adalimumab and baseline monocyte membrane TNF expression in patients before adalimumab treatment (n = 19). B, Membrane TNF expression on CD14+ monocytes isolated before adalimumab treatment from responders (n = 14) and nonresponders to therapy (n = 5). C, Monocyte membrane TNF expression at baseline from patients who responded to adalimumab therapy (n = 14), divided according to concurrent methotrexate therapy. D, In vitro effect of methotrexate on monocyte membrane TNF expression in PBMCs from untreated patients with RA (n = 12). E, ROC-curve analysis of the utility of baseline membrane TNF expression before therapy to predict response to adalimumab (n = 19). F, Adalimumab binding to monocytes from patients before treatment divided according to their clinical response to adalimumab (n = 18). G, ROC-curve analysis of the percentage binding of adalimumab to monocytes to predict response to adalimumab (n = 18). H, Monocyte membrane expression after culture with adalimumab or etanercept using PBMCs taken before adalimumab therapy, divided according to subsequent response (n = 14) or not (n = 5) to adalimumab. ROC, Receiver-operating characteristic. *P < .05; **P < .01; ***P < .001 by paired t test or Mann-Whitney test. Journal of Allergy and Clinical Immunology 2018 142, 978-980.e9DOI: (10.1016/j.jaci.2018.04.026) Copyright © 2018 The Authors Terms and Conditions

Fig E3 Adalimumab enhanced monocyte membrane TNF expression and increased Treg-cell frequency through an IL-10/p38-dependent mechanism. A, Monocyte p-p38 expression in methotrexate-treated RA PBMCs after stimulation with adalimumab in vitro. The results were divided according to whether the frequency of CD4+Foxp3+ Treg cells increased by more than 40% (n = 14) or not (n = 5) in response to adalimumab. B, Ex vivo p-p38 in CD14+ monocytes from patients responding to methotrexate (n = 14), adalimumab (n = 9), or etanercept (n = 5). C, Correlation between monocyte membrane TNF and p-p38 expression in PBMCs from patients treated with methotrexate cultured with adalimumab (n = 20). D, Ex vivo correlation between monocyte membrane TNF and p-p38 expression in monocytes from patients responding to methotrexate (n = 14) or to adalimumab therapy (n = 9). E, Representative FACS plot and cumulative data of IL-10 production by monocytes stimulated with adalimumab ± a p38 inhibitor (inh), or stimulated with etanercept (n = 9). F, Ex vivo IL-10 production by monocytes from patients responding to DMARD (n = 15), to adalimumab (n = 7), or to etanercept (n = 3). The effects of p38 inhibition and/or IL-10 blockade on (G) monocyte membrane TNF expression and (H) Treg-cell frequency from patients who responded to adalimumab (n = 7). DMARD, Disease-modifying antirheumatic drug. *P < .05; **P < .01; ***P < .001 by paired t test or Mann-Whitney test. Journal of Allergy and Clinical Immunology 2018 142, 978-980.e9DOI: (10.1016/j.jaci.2018.04.026) Copyright © 2018 The Authors Terms and Conditions

Fig E4 Flow cytometry gating strategy for CD4+FoxP3+ Treg cells and total p38 expression within monocytes. A, Gating strategy to reveal CD4+Foxp3+ Treg cells following in vitro stimulation with adalimumab. B, Representative histograms of CD4+ T cells stained with LIVE/DEAD fixable dead cell stain, from an RA PBMC sample cultured with adalimumab, etanercept, or without stimulation for 3 days. C, Histogram and cumulative data of total p38 expression in CD14+ monocytes in PBMCs from patients with RA treated with methotrexate following stimulation with adalimumab, where Treg cells increased by more than 40% or etanercept in vitro (n = 8). D, Total p38 expression from PBMCs isolated ex vivo from different patient groups (methotrexate, n = 14; adalimumab, n = 6; etanercept, n = 5). FSC, Forward scatter; SSC, side scatter. Journal of Allergy and Clinical Immunology 2018 142, 978-980.e9DOI: (10.1016/j.jaci.2018.04.026) Copyright © 2018 The Authors Terms and Conditions